ABSTRACT
Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ~3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance.
Subject(s)
Aging/pathology , Dexamethasone/adverse effects , Fetal Growth Retardation/physiopathology , Heart/drug effects , Prenatal Exposure Delayed Effects/physiopathology , Animals , Blood Pressure/drug effects , Female , Fetal Growth Retardation/chemically induced , Fetal Growth Retardation/metabolism , Fetus , Gene Expression/drug effects , Gestational Age , Heart/physiopathology , Humans , Insulin-Like Growth Factor I/agonists , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/drug effects , Nephrons/drug effects , Organ Size/drug effects , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/metabolism , Receptors, Adrenergic, alpha-1/genetics , Receptors, Adrenergic, alpha-1/metabolism , bcl-2-Associated X Protein/agonists , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
Vitamin D deficiency is a major worldwide public health problem affecting people of all ages, from infants to the elderly. Of particular concern is the high incidence of vitamin D deficiency in women during pregnancy and lactation, leading to the exposure of the growing fetus/infant to inadequate levels of vitamin D, which is essential for normal development. Vitamin D deficiency in adulthood is linked to the etiology of hypertension and to a multitude of adverse cardiovascular outcomes. It is now well-established that the antecedents of cardiovascular disease can originate very early in life. The purpose of this review is to highlight how maternal vitamin D deficiency, and its effects in upregulating the fetal renin-angiotensin system and altering cardiomyocyte growth in the fetal heart, has the potential to program long-term vulnerability to cardiovascular disease.
Subject(s)
Cardiovascular Diseases/etiology , Fetal Heart/metabolism , Myocytes, Cardiac/metabolism , Pregnancy Complications , Prenatal Exposure Delayed Effects , Prenatal Nutritional Physiological Phenomena , Vitamin D Deficiency/complications , Vitamin D/metabolism , Adult , Age Factors , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Female , Fetal Heart/growth & development , Humans , Infant , Infant, Newborn , Lactation , Pregnancy , Pregnancy Complications/metabolism , Pregnancy Complications/physiopathology , Renin-Angiotensin System , Risk Factors , Vitamin D Deficiency/metabolism , Vitamin D Deficiency/physiopathologyABSTRACT
A reduced complement of cardiomyocytes in early life can adversely affect life-long cardiac functional reserve. In the present study, using a cross-fostering approach in rats, we examined the contributions of the prenatal and postnatal environments in the programming of cardiomyocyte growth. Rat dams underwent either bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of gestation. One day after birth, Control and Restricted pups were cross-fostered onto Control (normal lactation) or Restricted (impaired lactation due to impaired mammary gland formation) mothers. In male offspring, genes involved in cardiomyocyte differentiation, proliferation, hypertrophy and apoptosis were examined at gestational day 20 and postnatal days 1 and 7 to assess effects on cardiomyocyte growth. At postnatal day 7 cardiomyocyte number was determined stereologically. Offspring were examined at age 6 mo for evidence of hypertension and pathological cardiac gene expression. There was an increase in Igf1 and Igf2 mRNA expression in hearts of Restricted pups at gestational day 20. At postnatal day 7, Agtr1a and Agtr1b mRNA expression as well as Bcl2 and Cmyc were elevated in all hearts from offspring that were prenatally or postnatally growth restricted. There was a significant reduction (-29%) in cardiomyocyte number in the Restricted-on-Restricted group. Importantly, this deficit was prevented by optimization of postnatal nutrition (in the Restricted-on-Control group). At 6 mo, blood pressure was significantly elevated in the Restricted-on-Restricted group, but there was no difference in expression of the cardiac hypertrophy, remodeling or angiogenic genes across groups. In conclusion, the findings reveal a critical developmental window, when cardiomyocytes are still proliferating, whereby improved neonatal nutrition has the capacity to restore cardiomyocyte number to normal levels. These findings are of particular relevance to the preterm infant who is born at a time when cardiomyocytes are immature and still dividing.
Subject(s)
Breast Feeding , Infant, Premature/physiology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Placental Insufficiency/pathology , Placental Insufficiency/physiopathology , Animals , Animals, Newborn , Cell Count , Female , Humans , Infant, Newborn , Lactation/physiology , Male , Placental Circulation , Pregnancy , Rats , Rats, Inbred WKYABSTRACT
The aim of this study was to determine the effect of vitamin D deficiency from conception until 4 weeks of age on the development of the heart in rat offspring. Sprague-Dawley (SD) rats were fed either a vitamin D deplete or vitamin D-replete diet for 6 weeks prior to pregnancy, during pregnancy and throughout lactation. Cardiomyocyte number was determined in fixed hearts of offspring at postnatal day 3 and 4 weeks of age using an optical disector/fractionator stereological technique. In other litters, cardiomyocytes were isolated from freshly excised hearts to determine the proportion of mononucleated and binucleated cardiomyocytes. Maternal vitamin D deficiency had no effect on cardiomyocyte number, cardiomyocyte area, or the proportion of mononucleated/binucleated cardiomyocytes in 3-day-old male and female offspring. Importantly, however, vitamin D deficiency led to an increase in left ventricle (LV) volume that was accompanied by an increase in cardiomyocyte number and size, and in the proportion of mononucleated cardiomyocytes at 4 weeks of age. Our findings suggest that exposure to vitamin D deficiency in utero and early life leads to delayed maturation and subsequent enhanced growth (proliferation and hypertrophy) of cardiomyocytes in the LV. This may lead to altered cardiac function later in life.
